Recently, there has been a revolution in biotechnology that is producing an abundance of potent new protein, peptide, and DNA-based drugs. Efficient, convenient, and effective means of delivering such therapeutics, however, are still needed.
Biodegradable polymers have been used for many applications in medicine, including controlled release drug delivery systems, resorbable bone pins and screws, and scaffolds for cells in tissue engineering. Systems based on biodegradable polymers obviate the need for surgical removal since their degradation products are absorbed or metabolized by the body. Micro- and nano-sized systems made using polymers can be used to deliver precise amounts of drugs, including small molecules, proteins and genes, over prolonged periods to local tissues or the systemic circulation. Of particular interest is the development of drug delivery vehicles that exhibit reduced detection rates by the immune system (e.g., long-circulating carriers for intravenous administration), or that can be administered via non-invasive delivery routes (such as inhalation). Biodegradable polymers that safely erode in the body, preferably at a rate that closely coincides with the rate of drug delivery, are required for these advanced applications.
Despite their wide and growing need in medicine, few synthetic biodegradable polymers are currently used routinely in humans, especially the ester copolymers of lactide and glycolide (PLGA family), and anhydride copolymers of sebacic acid (SA) and 1,3-bis(carboxyphenoxy)-propane (CPP). PLGA is the most widely used due to its history of safe use as surgical sutures and in current drug delivery products like the Lupron Depot. While the development of PLGA remains among the most important advances in medical biomaterials, there are some limitations that significantly curtail its use. First, PLGA particles typically take a few weeks to several months to completely degrade in the body, but the device is typically depleted of drug more rapidly. Repeated dosing of such a system leads to an unwanted build up of drug-depleted polymer in the body. This may preclude the use of PLGA for many applications, especially those that require injection of polymer drug carriers into the blood or, alternatively, their inhalation into the lungs. A second limitation is that PLGA devices undergo bulk-erosion, which leads to a variety of undesirable outcomes including exposure of unreleased drug to a highly acidic environment. Third, it is difficult to release drugs in a continuous manner from PLGA particles owing the polymers' bulk-erosion mechanism. Instead, special preparation methods are required with PLGA to avoid the typical intermittent drug release pattern (i.e., burst of drug followed by a period of little or no drug release, and then by the onset of a second phase of significant drug release). Fourth, the particularly fine PLGA particles needed for intravenous injection or inhalation can agglomerate significantly, making resuspension for injection or aerosolization for inhalation difficult. Finally, small, insoluble particles with hydrophobic surfaces, like those made with PLGA, are rapidly removed and destroyed by the immune system (due to fast opsonization).
Implants composed of poly(CPP:SA) were approved for use in humans in the 1990's to deliver chemotherapeutic molecules directly at the site of a resected brain tumor. CPP:SA copolymers erode from the surface-in (called surface-erosion), leading to desirable steady drug delivery rates over time. Proven biocompatibility, current clinical use, and steady drug release profiles make polymers composed of CPP and SA good candidates for new drug delivery applications. However, like PLGA particles, small particles made with poly(CPP:SA) possess hydrophobic surfaces that lead to rapid removal by the immune system and poor resuspension and aerosolization properties.
Hanes et al in USPA 2003/0086895 describes random copolymers of polyethylene glycols (PEG), sebacic acid, and, optionally, 1,3-bis(carboxyphenoxy)propane. These random copolymers have numerous medical uses (e.g., biodegradable drug delivery). However, due to the random incorporation of PEG into the copolymer, there is no free end of the PEG available for further manipulation. Such a free end would allow one of ordinary skill in the art to attach groups with desirable activities (e.g., targeting ligands or anti cancer drugs).